Abstract Teriparatide (PTH1-34) and Abaloparatide (modified PTHrP1-34) are approved anabolic drugs for the treatment of osteoporosis, a widespread bone fragility chronic condition linked to aging, with important health and socio-economic consequences. Osteoporosis and aging involve dysfunctions of cells in bone, often associated with an increase in bone marrow adipose tissue (BMAT). Estrogen deficiency, glucocorticoid treatment or decreased mechanical loading lower bone mass but also increase BMAT. PTH and WNT signaling oppose both effects, further suggesting a clinical link between low bone mass and high marrow adiposity. The maintenance of bone mass is essential for the prevention of osteoporosis and fractures in the elderly, whereas the consequences of excessive BMAT are still not understood. Because osteoblasts (OBs) and adipocytes (ADs) share a common precursor in the mesenchymal stem cell (MSC) lineage it is thought that the increase in bone marrow ADs is linked to the decrease in OB differentiation. Moreover, MSCs derived from bone marrow or from fat are used in bone regeneration, and PTH is now widely used clinically for fracture healing. The mechanisms by which PTH favors bone at the expense of BMAT and the role of BMAT reduction in the response of bone to PTH are however not known. Characterization of novel downstream PTH effectors in MSCs for the OB versus AD cell fate decision and in the crosstalk between PTH and WNT could have a significant impact on the development or understanding of anabolic osteoporosis treatment as well as on the use of MSCs for bone regeneration. The proposed work is innovative because it focuses on the anti- adipogenic responses to PTH/PTHrP treatment and their implication in anabolic responses of the skeleton. The main goal of this application is to identify the components of the signal transduction machinery that allows intermittent PTH (iPTH) to promote bone formation and repress BMAT, in order to determine whether interfering with the anti-adipogenic factor Zfp521 or the pro-adipogenic factors Zfp467 and Zfp423, can enhance the therapeutic effects of treatment with iPTH, i.e. whether preventing the AD differentiation may enhance the anabolic effects of iPTH. We will determine whether enhancing (via deletion of the anti-ADgenic factor Zfp521) or blocking (via deletion of the pro-ADgenic factors Zfp467 or Zfp423) pro-adipogenic signals downstream of the PPR could impair or favor, respectively, the bone anabolic responses to iPTH treatment. To this end, we will identify the PPR signaling events that repress adipogenic targets in order to possibly improve bone anabolic responses by enhancing the anti-adipogenic effects of iPTH. For this reason, and since we have identified three key regulators of adipogenesis in MSCs, we propose to dissect the signaling pathways downstream of the PPR that lead to the increased expression of Zfp521 and the repression of Zfp467 and Zfp423. !